The University of Colorado Cancer Center (UCCC), in its 29th year of NCI designation, has built on its ?excellent? overall rating in 2011, with major scientific advances and national leadership. Serving the catchment area of the State of Colorado, UCCC, a matrix within the School of Medicine, is a multidisciplinary research consortium of the University of Colorado at Denver and Boulder, Colorado State University and clinical affiliates University of Colorado Hospital, Children?s Hospital Colorado and the Denver VA. The UCCC achieves its mission to discover, develop, and deliver breakthroughs in cancer science through interdisciplinary collaborative research. UCCC discoveries with potential to change cancer medicine include: 1) role of COX-2 in driving progression of in situ disease to breast carcinoma with a prevention trial being developed; 2) molecular basis of radiation mucositis translated into treatment strategies for survivors; 3) ?first in class? inhibitor of Ral, a previously deemed ?undrugable? GTPase known to drive many pancreatic, colon and lung cancers, now in commercial development; 4) role of androgen receptor in breast cancer, leading to a DOD Clinical Translational Research Award and national trial of oral antiandrogens in triple negative cancers; 5) showing genotype-directed therapy in lung cancer leads to better survival; 6) novel therapeutic combinations in Investigator Initiated Trials (IIT) in multiple cancers, developed from synthetic lethal functional genomic screens. The UCCC?s national leadership and recognition include our Lung SPORE, LAPS U10 and ET-CTN UM1 grants supporting NCTN and CTEP trials, a SPECS U01 grant, election into the NCCN, and rise to 15th adult cancer program in USNWR. The UCCC has 196 (28 new) Full members, representing 96% of all NCI-funded PIs in CO, in 6 programs: Molecular Oncology (MO); Cancer Cell Biology (CCB); Developmental Therapeutics (DT); Hematologic Malignancies (HEME); Lung, Head & Neck Cancer (LHN), and Cancer Prevention and Control (CPC). Since July 2011, 2,636 publications (22% inter- and 25% intra-programmatic) were produced with 15% having high (>9.6 IF) impact (13% previously), 88 patents issued, 26 licenses negotiated (104% and 116% increase), 15 startup companies founded and 47 intervention IITs opened. In 2015, members held $52M in direct peer-reviewed cancer funding (24% increase in # of NCI grants), accrued 1499 subjects (52% increase) to intervention trials and 706/3946 newly registered patients (18%) to intervention treatment trials. 10 Shared Resources that leverage institutional and NIH investments support UCCC research. Skillful management, recruitments, a $74M investment and 3 new endowed chairs, addressed NCI site visit and EAB concerns. Future directions include multidisciplinary initiatives to promote healthy living, tackle resistance to targeted agents, enhance immunotherapy, leverage comparative oncology, expand cancer bioengineering and develop a statewide clinical research network. CCSG renewal and new institutional commitments of $65M and 20K sf of space will allow the UCCC to maintain its upward trajectory of high impact contributions and help reduce the cancer burden in its catchment area and worldwide.